Novel guanidino compounds

ABSTRACT

Compounds having he general structure I are provided. X and Y are independently selected from the group consisting of CH 2 , N, NR 9 , C═O, C═S, S═O, SO 2 , S, O, (CR 6 R 7 ) n , C(═O)—(CR 6 R 7 ) n , and C(═S)—(CR 6 R 7 ) n , where n is 1, 2, or 3. W is selected from the group consisting of (formula I) and L is selected from the group consisting of N, O, S═O, SO, C(O), NC(O), NC(S), OC(O), OC(S), C(NR 10 ), C(NOR 10 ), and a covalent bond. Z 1 , Z 2 , and Z 3  are independently selected from the group consisting of substituted carbon and nitrogen. Compounds of formula I are agonists of the melanocortin-4 receptor (″MC-4r2) and therefore may have useful properties for controlling diseases related to MC-4r action in humans, such as obesity and type II diabetes.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationNo. 60/282,847 filed Apr. 9, 2001, the entire disclosure of which isincorporated herein by reference and for all purposes.

FIELD OF THE INVENTION

[0002] This invention relates to melanocortin-4 receptor (MC4-R)agonists and methods of their preparation. The invention also relates tomethods of treating melanocortin-4 receptor-mediated diseases, such asobesity or diabetes, by activating the melanocortin-4 receptor withcompounds provided herein.

BACKGROUND OF THE INVENTION

[0003] Melanocortins are peptide products resulting frompost-translational processing of pro-opiomelanocortin and are known tohave a broad array of physiological activities. The naturalmelanocortins include the different types of melanocyte stimulatinghormone (α-MSH, β-MSH, γ-MSH) and ACTH. Of these, α-MSH and ACTH areconsidered to be the main endogenous melanocortins.

[0004] The melanocortins mediate their effects through melanocortinreceptors (MC-R), a subfamily of G-protein coupled receptors. There areat least five different receptor subtypes (MC1-R to MC5-R). MC1-Rmediates pigmentation of the hair and skin. MC2-R mediates the effectsof ACTH on steroidogenisis in the adrenal gland. MC3-R and MC4-R arepredominantly expressed in the brain. MC5-R is considered to have a rolein the exocrine gland system.

[0005] The melanocortin-4 receptor (MC4-R) is a seven-transmembranereceptor. MC4-R may participate in modulating the flow of visual andsensory information, coordinate aspects of somatomotor control, and/orparticipate in the modulation of autonomic outflow to the heart. Science1992 257:1248-125. Significantly, inactivation of this receptor by genetargeting has resulted in mice that develop a maturity onset obesitysyndrome associated with hyperphagia, hyperinsulinemia, andhyperglycemia. Cell 1997 Jan 10; 88(1): 13141. MC4-R has also beenimplicated in other disease states including erectile disorders,cardiovascular disorders, neuronal injuries or disorders, inflammation,fever, cognitive disorders, and sexual behavior disorders. Hadley M. E.and Haskell-Luevano C., The proopiomelanocortin system. Ann N Y AcadSci, 1999 Oct. 20;885:1.

[0006] Furthermore, observations in connection with endogenous MCx-Rantagonists indicate that MC4-R is implicated in endogenous energyregulation. For example, an agouti protein is normally expressed in theskin and is an antagonist of the cutaneous MC receptor involved inpigmentation, MC1-R. M. M. Ollmann et al., Science, 278:135-138 (1997).However, overexpression of agouti protein in mice leads to a yellow coatcolor due to antagonism of MC1-R and increased food intake and bodyweight due to antagonism of MC4-R. L. L. Kiefer et al., Biochemistry,36: 2084-2090(1997); D. S. Lu et al., Nature, 371:799-802 (1994). Agoutirelated protein (AGRP), an agouti protein homologue, antagonizes MC4-Rbut not MC1 -R. T. M. Fong et al., Biochem. Biophys. Res. Commun.237:629-631 (1997). Administration of AGRP in mice increases food intakeand causes obesity but does not alter pigmentation. M. Rossi et al.,Endocrinology, 139:4428-4431 (1998). Together, this research indicatesthat MC4-R participates in energy regulation, and therefore, identifiesthis receptor as a target for a rational drug design for the treatmentof obesity.

[0007] In connection with MC4-R and its uncovered role in the etiologyof obesity and food intake, the prior art has reported compounds orcompositions that act as agonists or antagonists of MC4-R. As examples,U.S. Pat. No. 6,060,589 describes polypeptides that are capable ofmodulating signaling activity of melanocortin receptors. Also, U.S. Pat.Nos. 6,054,556 and 5,731,408 describe families of agonists andantagonists for MC4-R receptors that are lactam heptapeptides having acyclic structure.

[0008] There is a need to for potent and specific agonists of MC-R thatare low molecular weight non-peptide small molecules. Methods oftreating a melanocortin4 receptor mediated disease, such as obesity,with such non-peptide drugs, are also particularly desirable.

SUMMARY OF THE INVENTION

[0009] The instant invention provides potent and specific agonists ofMC4-R that are low molecular weight non-peptide small molecules. Thus,there has been provided, in accordance with one aspect of the invention,a compound of formula I:

[0010] wherein

[0011] X and Y are independently selected from the group consisting ofCH₂, N, NR⁹, C═O, C═S, S═O, SO₂, S, O, (CR⁶R⁷)_(n), C═O)—(CR⁶R⁷)_(n,)and C(═S)—(CR⁶R⁷)_(n);

[0012] n is 1, 2, or 3;

[0013] W is selected from the group consisting of

[0014] L is selected from the group consisting of N, O, S, S═O, SO₂,C(O), NC(O), NC(S), OC(O), OC(S), C(NR¹⁰), C(NOR¹⁰), and a covalentbond;

[0015] Z¹, Z², and Z³ are independently selected from the groupconsisting of CR⁸ and N;

[0016] R¹ is selected from the group consisting of H, and substitutedand unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclytalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups;

[0017] R² is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, andarylalkyl groups;

[0018] R³ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, andcycloalkylalkyl groups, or R² and R³ may join together to form a ringcontaining at least two N atoms;

[0019] R⁴ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR² and R⁴ may join together to form a ring containing at least two Natoms;

[0020] R⁵ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl or heteroaryl group, or R³ andR⁵ may join together to form a ring containing at least two N atoms;

[0021] R⁶ and R⁷ may be the same or different, and are eachindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;

[0022] R⁸ is independently selected from the group consisting of H, Cl,I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy,amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; and

[0023] R⁹ and R¹⁰ are independently selected from the group consistingof H, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, alkylcarbonyl, and arylcarbonyl groups.

[0024] Compounds provided by the invention further include prodrugs ofthe compound of formula I, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, hydrates thereof, hydridesthereof, or solvates thereof.

[0025] In one embodiment, X is CH₂ and Y is C═O.

[0026] In another embodiment, X is C═O and Y is CH₂.

[0027] In another embodiment, X is C═O and Y is C═O.

[0028] In other embodiments, L is a covalent bond, and X and Y have thevalues according to any of the previous embodiments.

[0029] In another embodiment, Z¹, Z², and Z³ are all CH, and X, Y, and Lhave the values according to any of the previous embodiments.

[0030] In another embodiment, at least one of Z¹, Z², or Z³ is N, and X,Y, and L have the values according to any of the previous embodiments.

[0031] In another embodiment, X, Y, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of substituted and unsubstituted arylalkyl, alkenyl,heteroarylalkyl, and heterocyclylalkyl groups.

[0032] In another embodiment, X, Y, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is 2,4-disubstituted phenethyl.

[0033] In another embodiment, X, Y, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of 2,4-dihalophenethyl, and 2,4-dialkylphenethyl.

[0034] In another embodiment, X, Y, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of phenethyl, 2,4-dichlorophenethyl, 4-methoxyphenethyl,4-bromophenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4-chlorobenzyl,4-ethylphenethyl, cyclohexenylethyl, 2-methoxyphenethyl,2-chlorophenethyl, 2-fluorophenethyl, 3-methoxyphenethyl,3-fluorophenethyl, thienylethyl, indolylethyl, 4-hydroxyphenethyl, and3,4-dimethoxyphenethyl.

[0035] In another embodiment, X, Y, L, Z¹, Z², Z³, and R¹ have any ofthe values of previous embodiments, and R² is H.

[0036] In another embodiment, X, Y, L, Z¹, Z², Z³ R, and R² have any ofthe values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups.

[0037] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, and R² have anyof the values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted cycloalkyl, alkenyl, alkyl,and aryl groups.

[0038] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, and R² have anyof the values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted cyclohexyl,2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl,2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl,3,4-dialkylcyclohexyl, 3-alkylcyclohexyl, 4-alkylcyclohexyl,3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, cyclopentyl, cycloheptyl, cyclohexenyl,isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl,2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl,adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl,norbornyl, and decalinyl groups.

[0039] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, and R² have anyof the values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted cyclohexyl,2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl,2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl,3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,cyclohex-3-enyl, 3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl,2-methylcycloheptyl, cyclohexylmethyl, isopinocampheyl,7,7-dimethylnorbornyl, 4-isopropylcyclohexyl,2,6,6-trimethylbicyclo[3.1.1]heptyl, and 3-methylcycloheptyl.

[0040] In another embodiment, X, Y, L, Z¹ Z², Z³, R¹, R², and R³have anyof the values of previous embodiments, and R⁵ is selected from the groupconsisting of substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl,and cycloalkylalkyl groups.

[0041] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituted alkyl,arylalkyl, and heteroarylalkyl groups.

[0042] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁹ is selectedfrom the group consisting of substituted and unsubstituteddialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,3-methylbenzyl, benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,and thiophene groups.

[0043] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups.

[0044] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophenegroups.

[0045] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a substituted orunsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group.

[0046] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a piperazino group optionallysubstituted by one or two alkyl groups, for example, one or two methylgroups.

[0047] There has also been provided, in accordance with another aspectof the invention, a compound of formula II:

[0048] wherein

[0049] A is selected from the group consisting of C or CH;

[0050] X and Y are independently selected from the group consisting ofCH₂, N, C═O, C═S, (CR⁶R⁷)_(n), S═O, SO₂, O, NR⁹, S, C(═O)—(CR⁶R⁷)_(n),and C(═S)—(CR⁶R⁷)_(n);

[0051] n is 1, 2, or 3;

[0052] W is selected from the group consisting of

[0053] Z¹, Z², and Z³ are independently selected from the groupconsisting of CR⁸ and N;

[0054] L is selected from the group consisting of N, O, S, S═O, SO₂,C(O), NC(O), NC(S), OC(O), OC(S), C(NR¹⁰), C(NOR¹⁰), and a covalentbond;

[0055] R¹ is selected from the group consisting of H, and substitutedand unsubstituted arylalkyl, heteroarylalkyl, aryl, heterocyclyl,cycloalkyl,. heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, andalkyl groups;

[0056] R² is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, andarylalkyl groups;

[0057] R³ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, andcycloalkylalkyl groups, or R² and R³ may join together to form a ringcontaining at least two N atoms;

[0058] R⁴ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR² and R⁴ may join together to form a ring containing at least two Natoms;

[0059] R⁵ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl or heteroaryl group, or R³ andR⁵ may join together to form a ring containing at least two N atoms;

[0060] R⁶ and R⁷ may be the same or different, and are eachindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;

[0061] R⁸ is independently selected from the group consisting of H, Cl,I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy,amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; and

[0062] R⁹ and R¹⁰ are independently selected from the group consistingof H, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, alkylcarbonyl, and arylcarbonyl groups.

[0063] Compounds provided by the invention further include prodrugs ofthe compound of formula II, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, hydrates thereof, hydridesthereof, or solvates thereof.

[0064] In one embodiment, X is N, Y is NH, A is C, and the bond betweenX and A is a double bond.

[0065] In another embodiment, X is NH, Y is N, A is C, and the bondbetween Y and A is a double bond.

[0066] In another embodiment, A is C and the bond between either A and Xor between A and Y is a double bond.

[0067] In another embodiment, X, Y, and A have any of the values ofprevious embodiments, and L is a covalent bond.

[0068] In another embodiment, X, Y, A, and L have any of the values ofprevious embodiments, and Z¹, Z², and Z³ are all CH.

[0069] In another embodiment, X, Y, A, and L have any of the values, ofprevious embodiments, and at least one of Z¹, Z², or Z³ is N.

[0070] In another embodiment, X, Y, A, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of substituted and unsubstituted arylalkyl, alkenyl,heteroarylalkyl, and heterocyclylalkyl groups.

[0071] In another embodiment, X, Y, A, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is 2,4-disubstituted phenethyl.

[0072] In another embodiment, X, Y, A, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of 2,4-dihalophenethyl, and 2,4-dialkylphenethyl.

[0073] In another embodiment, X, Y, A, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of phenethyl, 2,4-dichlorophenethyl, 4-methoxyphenethyl,4-bromophenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4-chlorobenzyl,4-ethylphenethyl, cyclohexenylethyl, 2-methoxyphenethyl,2-chlorophenethyl, 2-fluorophenethyl, 3-methoxyphenethyl,3-fluorophenethyl, thienylethyl, indolylethyl, 4-hydroxyphenethyl, and3,4-dimethoxyphenethyl.

[0074] In another embodiment, X, Y, A, L, Z¹, Z², Z³, and R¹ have any ofthe values of previous embodiments, and R² is H.

[0075] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups.

[0076] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cycloalkyl, alkenyl,alkyl, and aryl groups.

[0077] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cyclohexyl,2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl,2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl,3,4-dialkylcyclohexyl, 3-alkylcyclohexyl, 4-alkylcyclohexyl,3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, cyclopentyl, cycloheptyl, cyclohexenyl,isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl,2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl,adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl,norbornyl, and decalinyl groups.

[0078] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹ and R² have anyof the values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted cyclohexyl,2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl,2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl,3,4dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,cyclohex-3-enyl, 3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl,2-methylcycloheptyl, cyclohexylmethyl, isopinocampheyl,7,7-dimethylnorbornyl, 4-isopropylcyclohexyl,2,6,6-trimethylbicyclo[3.1.1heptyl, and 3-methylcycloheptyl.

[0079] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁵ is selected from thegroup consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups.

[0080] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³haveany of the values of previous embodiments, R⁴ is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituted alkyl,arylalkyl, and heteroarylalkyl groups.

[0081] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituteddialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,3-methylbenzyl, benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,and thiophene groups.

[0082] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups.

[0083] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R²and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophenegroups.

[0084] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a substituted orunsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group.

[0085] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a piperazino group optionallysubstituted by one or two alkyl groups, for example, one or two methylgroups.

[0086] There has also been provided, in accordance with another aspectof the invention, a compound of formula III:

[0087] wherein

[0088] X and Y are independently selected from the group consisting ofCH₂, N, C═O, NR⁹, C═S, S═O, SO₂, O, S, (CR⁶R⁷)_(n), C(═O)—(CR⁶R⁷)_(n),and C(═S)—(CR⁶R⁷)_(n);

[0089] D is selected from the group consisting of N, and C;

[0090] If X is N, then Y is not N, but may be NH;

[0091] If Y is N, then X is not N, but may be NH;

[0092] If X is CH₂, then Y is not CH₂;

[0093] If Y is CH₂, then X is not CH₂;

[0094] If X is NH, then Y is not NH;

[0095] If Y is NH, then X is not NH;

[0096] L is selected from the group consisting of N, O, S, S═O, SO₂,C(O), NC(O), NC(S), OC(O), OC(S), C(NR¹⁰), C(NOR¹⁰), and a covalentbond;

[0097] W is selected from the group consisting of

[0098] Z¹, Z², and Z³ are independently selected from the groupconsisting of CR⁸ and N;

[0099] R¹ is selected from the group consisting of H, and substitutedand unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups;

[0100] R² is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, andarylalkyl groups;

[0101] R³ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, andcycloalkylalkyl groups, or R² and R³ may join together to form a ringcontaining at least two N atoms;

[0102] R⁴ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR² and R⁴ may join together to form a ring containing at least two Natoms;

[0103] R⁵ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl or heteroaryl group, or R3 andR⁵ may join together to form a ring containing at least two N atoms;

[0104] R⁶ and R⁷ may be the same or different, and are eachindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;

[0105] R⁸ is independently selected from the group consisting of H, Cl,I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy,amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; and

[0106] R⁹ and R¹⁰ are independently selected from the group consistingof H, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, alkylcarbonyl, and arylcarbonyl groups.

[0107] Compounds provided by the invention further include prodrugs ofthe compound of formula II, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, hydrates thereof, hydridesthereof, or solvates thereof.

[0108] In one embodiment, X is CH₂, Y is C═O, and D is N.

[0109] In another embodiment, X is C═O, Y is CH₂, and D is N.

[0110] In another embodiment, X is C═O, Y is C═O, and D is N.

[0111] In another embodiment, X is N, Y is NH, D is C, and the bondbetween X and D is a double bond.

[0112] In another embodiment, X is NH, Y is N, D is C, and the bondbetween Y and D is a double bond.

[0113] In another embodiment, X, Y, and D have any of the values ofprevious embodiments, and L is a covalent bond.

[0114] In another embodiment, X, Y, D, and L have any of the values ofprevious embodiments, and Z¹, Z², and Z³ are all CH.

[0115] In another embodiment, X, Y, D, and L have any of the values ofprevious embodiments, and at least one of Z¹, Z², or Z³ is N.

[0116] In another embodiment, X, Y, D, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of substituted and unsubstituted arylalkyl, alkenyl,heteroarylalkyl, and heterocyclylalkyl groups.

[0117] In another embodiment, X, Y, D, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is 2,4-disubstituted phenethyl.

[0118] In another embodiment, X, Y, D, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of 2,4-dihalophenethyl, and 2,4-dialkylphenethyl.

[0119] In another embodiment, X, Y, D, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of phenethyl, 2,4-dichlorophenethyl, 4-methoxyphenethyl,4-bromophenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4-chlorobenzyl,4-ethylphenethyl, cyclohexenylethyl, 2-methoxyphenethyl,2-chlorophenethyl, 2-fluorophenethyl, 3-methoxyphenethyl,3-fluorophenethyl, thienylethyl, indolylethyl, 4-hydroxyphenethyl, and3,4-dimethoxyphenethyl.

[0120] In another embodiment, X, Y, D, L, Z¹, Z², Z³, and R¹ have any ofthe values of previous embodiments, and R² is H.

[0121] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, heterocyclyl,heterocyclylalkyl;,arylalkyl, heteroarylalkyl, and cycloalkylalkylgroups.

[0122] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cycloalkyl, alkenyl,alkyl, and aryl groups.

[0123] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cyclohexyl,2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl,2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl,3,4-dialkylcyclohexyl, 3-alkylcylohexyl, 4-alkylcyclohexyl,3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, cyclopentyl, cycloheptyl, cyclohexenyl,isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl,2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl,adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl,norbornyl, and decalinyl groups.

[0124] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cyclohexyl,2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl,2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl,3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,cyclohex-3-enyl, 3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl,2-methylcycloheptyl, cyclohexylmethyl, isopinocampheyl,7,7-dimethylnorbornyl, 4-isopropylcyclohexyl,2,6,6-trimethylbicyclo[3.1.1]heptyl, and 3-methylcycloheptyl.

[0125] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁵ is selected from thegroup consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups.

[0126] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituted alkyl,arylalkyl, and heteroarylalkyl groups.

[0127] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R²and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituteddialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,3-methylbenzyl, benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,and thiophene groups.

[0128] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R²and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups.

[0129] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,.and thiophenegroups.

[0130] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R²and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a substituted orunsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group.

[0131] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a piperazino group optionallysubstituted by one or two alkyl groups, for example, one or two methylgroups.

[0132] There has also been provided, in accordance with another aspectof the invention, a composition comprising a compound according to theinstant invention and a pharmaceutically acceptable carrier.

[0133] There has also been provided, in accordance with another aspectof the invention, a method of activating MC4-R, comprising administeringto a subject in need thereof, an effective amount of a compound orcomposition of the instant invention.

[0134] There has also been provided, in accordance with another aspectof the invention, a method of treating an MC4-R mediated disease,comprising administering to a subject in need thereof, a compound orcomposition of the instant invention.

[0135] In one embodiment, a disease to be treated by those methods ofthe instant invention is obesity, or type I or type II diabetes.

[0136] There has also been provided, in accordance with another aspectof the invention, a method of decreasing blood glucose levels,comprising administering to a subject in need thereof, a compound orcomposition of the instant invention.

[0137] In various alternative embodiments, the composition isadministered orally, rectally, by subcutaneous injection, by intravenousinjection, by intramuscular injection, or by intraperitoneal injection.

[0138] Other objects, features and advantages of the present inventionwill become apparent from the following detailed description. It shouldbe understood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0139] The instant invention relates to novel classes of small moleculemelanocortin-4 receptor (MC4-R) agonists. These compounds can beformulated into compositions and are useful in activating MC4-R, or inthe treatment of MC4-R-mediated diseases, such as obesity.

[0140] The following definitions are used throughout this specification:

[0141] Alkyl groups are straight chain lower alkyl groups having 1 toabout 8 carbon atoms, as exemplified by methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, and octyl. Alkyl groups also include branchedchain isomers of straight chain alkyl groups, including, but not limitedto, isopropyl, sec-butyl, t-butyl, isopentyl and so on. Representativesubstituted alkyl groups may be substituted one or more times with, forexample, amino, thio, alkoxy, or halo.

[0142] Cycloalkyl groups are cyclic alkyl groups such as, but notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups, and can include two or morebridgehead carbon atoms to form polycyclic rings (e.g., norbornyl orbicyclo[3.1.1]heptyl). Cycloalkyl groups also includes rings that aresubstituted with straight or branched chain alkyl groups as definedabove (e.g., bornyl or 2,6,6-trimethylbicyclo[3.1.1]heptyl).Representative substituted cycloalkyl groups may be mono-substituted orsubstituted more than once, such as, but not limited to, 2,2-, 2,3-,2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- ortri-substituted norbornyl or cycloheptyl groups, which may besubstituted with, for example, alkyl, alkoxy, amino, thio, or halogroups.

[0143] Alkenyl groups are straight chain, branched or cyclic lower alkylgroups having 2 to about 8 carbon atoms, and further including at leastone double bond, as exemplified, for instance, by vinyl, propenyl,2-butenyl, 3-butenyl, isobutenyl, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl groups amongothers.

[0144] Alkynyl groups are straight chain or branched lower alkyl groupshaving 2 to about 8 carbon atoms, and further including at least onetriple bond, as exemplified by groups, including, but not limited to,ethynyl, propynyl, and butynyl groups.

[0145] Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Thus aryl groups include, but are not limited to, phenyl,azulene, heptalene, biphenylene, indacene, fluorene, phenanthrene,triphenylene, pyrene, naphthacene, chrysene, biphenyl, anthracenyl, andnaphthenyl groups. Although the phrase “aryl groups” includes groupscontaining fused rings, such as fused aromatic-aliphatic ring systems,it does not include aryl groups that have other groups, such as alkyl orhalo groups, bonded to one of the ring members. Rather, groups such astolyl are referred to as substituted aryl groups. The phrase “arylgroups” includes groups bonded to one or more carbon atom(s), and/ornitrogen atom(s), in the compounds of formulas I and II. Representativesubstituted aryl groups may be mono-substituted or substituted more thanonce, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substitutedphenyl or benzyl groups, which may be substituted with groups including,but not limited to, amino, alkoxy, alkyl, or halo.

[0146] Cycloalkylalkyl groups are alkyl groups as defined above in whicha hydrogen or carbon bond of an alkyl group is replaced with a bond to acycloalkyl group as defined above.

[0147] Arylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to anaryl group as defined above.

[0148] Heterocyclyl groups are nonaromatic ring compounds containing 3or more ring members, of which, one or more is a heteroatom such as, butnot limited to, N, O, and S. The phrase “heterocyclyl group” includesfused ring species including those comprising fused aromatic andnonaromatic groups. However, the phrase does not include heterocyclylgroups that have other groups, such as alkyl or halo groups, bonded toone of the ring members. Rather, these are referred to as “substitutedheterocyclyl groups”. Heterocyclyl groups include, but are not limitedto, piperazino, morpholino, thiomorpholino, pyrrolidino, piperidino andhomopiperazino groups. Representative substituted heterocyclyl groupsmay be mono-substituted or substituted more than once, such as, but notlimited to morphilino or piperazino groups, which are 2-, 3-, 4-, 5-, or6-substituted, or disubstituted with groups including, but not limitedto, amino, alkoxy, alkyl, or halo.

[0149] Heteroaryl groups are aromatic ring compounds containing 3 ormore ring members, of which, one or more is a heteroatom such as, butnot limited to, N, O, and S. Heteroaryl groups include, but are notlimited to, groups such as furan, thiophene, pyrrole, isopyrrole,diazole, imidazole, isoimidazole, triazole, dithiole, oxathiole,isoxazole, oxazole, thiazole, isothiazole, oxadiazole, oxatriazole,dioxazole, oxathiazole, pyran, dioxin, pyridine, pyrimidine, pyridazine,pyrazine, triazine, oxazine, isoxazine, oxathiazine, azepin, oxepin,thiepin, diazepine, benzofuran, and isobenzofuran. Although the phrase“heteroaryl groups” includes fused ring compounds, the phrase does notinclude heteroaryl groups that have other groups bonded to one of thering members, such as alkyl groups. Rather, heteroaryl groups with suchsubstitution are referred to as “substituted heterocyclyl groups”.Representative substituted heterocyclyl groups may be substituted one ormore times with groups including, but not limited to, amino, alkoxy,alkyl, or halo.

[0150] Heterocyclylalkyl groups are alkyl groups as defined above inwhich a hydrogen or carbon bond of an alkyl group is replaced with abond to a heterocyclyl group as defined above.

[0151] Heteroarylalkyl groups are alkyl groups as defined above in whicha hydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above.

[0152] Aminocarbonyl groups are groups of the formula RR′NC(O)—, whereinR or R′ may be the same or different, and each is independently selectedfrom H, or substituted or unsubstituted alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl groups, as defined above.

[0153] In general, “substituted” refers to a group as defined above inwhich one or more bonds to a hydrogen atom contained therein arereplaced by a bond to non-hydrogen or non-carbon atoms such as, but notlimited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom ingroups such as hydroxyl groups, alkoxy groups, aryloxy groups, and estergroups; a sulfur atom in groups such as thiol groups, alkyl and arylsulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; anitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as in trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.Substituted alkyl groups and also substituted cycloalkyl groups alsoinclude groups in which one or more bonds to a carbon(s) or hydrogen(s)atom is replaced by a bond to a heteroatom such as oxygen in carbonyl,carboxyl, and ester groups; nitrogen in groups such as imines, oximes,hydrazones, and nitriles.

[0154] Substituted cycloalkyl, substituted aryl, substitutedheterocyclyl and substituted heteroaryl also include rings and fusedring systems which may be substituted with alkyl groups as definedabove. Substituted arylalkyl groups may be substituted on the arylgroup, on the alkyl group, or on both the aryl and alkyl groups.

[0155] The instant invention provides potent and specific agonists ofMC4-R that are low molecular weight non-peptide small molecules. Thus,there has been provided, in accordance with one aspect of the invention,a compound of formula I:

[0156] wherein

[0157] X and Y are independently selected from the group consisting ofCH₂, N, NR⁹, C═O, C═S, S═O, SO₂, S, O, (CR⁶R⁷)_(n), C(═O)—(CR⁶R⁷)_(n),and C(═S)—(CR⁶R⁷)_(n);

[0158] n is 1, 2, or 3;

[0159] W is selected from the group consisting of

[0160] L is selected from the group consisting of N, O, S, S═O, SO₂,C(O), NC(O), NC(S), OC(O), OC(S), C(NR¹⁰), C(NOR¹⁰), and a covalentbond;

[0161] Z¹, Z², and Z³ are independently selected from the groupconsisting of CR⁸ and N;

[0162] R¹ is selected from the group consisting of H, and substitutedand unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups;

[0163] R² is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, andarylalkyl groups;

[0164] R³ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, andcycloalkylalkyl groups, or R² and R³ may join together to form a ringcontaining at least two N atoms;

[0165] R⁴ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR² and R⁴ may join together to form a ring containing at least two Natoms;

[0166] R⁵ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl or heteroaryl group, or R³ andR⁵ may join together to form a ring containing at least two N atoms;

[0167] R⁶ and R⁷ may be the same or different, and are eachindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;

[0168] R⁸ is independently selected from the group consisting of H, Cl,I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy,amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; and

[0169] R⁹ and R¹⁰ are independently selected from the group consistingof H, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, alkylcarbonyl, and arylcarbonyl groups.

[0170] Compounds provided by the invention further include prodrugs ofthe compound of formula I, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, hydrates thereof, hydridesthereof, or solvates thereof.

[0171] In one embodiment, X is CH₂ and Y is C═O.

[0172] In another embodiment, X is C═O and Y is CH₂.

[0173] In another embodiment, X is C═O and Y is C═O.

[0174] In other embodiments, L is a covalent bond, and X and Y have thevalues according to any of the previous embodiments.

[0175] In another embodiment, Z¹, Z², and Z³ are all CH, and X, Y, and Lhave the values according to any of the previous embodiments.

[0176] In another embodiment, at least one of Z¹, Z², or Z³ is N, and X,Y, and L have the values according to any of the previous embodiments.

[0177] In another embodiment, X, Y, L, Z¹, Z², and Z³have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of substituted and unsubstituted arylalkyl, alkenyl,heteroarylalkyl, and heterocyclylalkyl groups.

[0178] In another embodiment, X, Y, L, Z¹, Z², and Z³have any of thevalues of previous embodiments, and R¹ is 2,4-disubstituted phenethyl.

[0179] In another embodiment, X, Y, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of 2,4-dihalophenethyl, and 2,4-dialkylphenethyl.

[0180] In another embodiment, X, Y, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of phenethyl, 2,4-dichlorophenethyl, 4-methoxyphenethyl,4-bromophenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4-chlorobenzyl,4-ethylphenethyl, cyclohexenylethyl, 2-methoxyphenethyl,2-chlorophenethyl, 2-fluorophenethyl, 3-methoxyphenethyl,3-fluorophenethyl, thienylethyl, indolylethyl, 4-hydroxyphenethyl, and3,4-dimethoxyphenethyl.

[0181] In another embodiment, X, Y, L, Z¹, Z², Z³, and R¹ have any ofthe values of previous embodiments, and R² is H.

[0182] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, and R² have anyof the values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups.

[0183] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, and R² have anyof the values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted cycloalkyl, alkenyl, alkyl,and aryl groups.

[0184] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, and R² have anyof the values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted cyclohexyl,2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl,2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl,3,4-dialkylcyclohexyl, 3-alkylcyclohexyl, 4-alkylcyclohexyl,3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl , 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, cyclopentyl, cycloheptyl, cyclohexenyl,isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl,2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl,adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl,norbornyl, and decalinyl groups.

[0185] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, and R² have anyof the values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted cyclohexyl,2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl,2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6dimethylcyclohexyl,3,4dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,cyclohex-3-enyl, 3,3,5-trimethylcyclohexyl, 4-t-buty(cyclohexyl,2-methylcycloheptyl, cyclohexylmethyl, isopinocampheyl,7,7-dimethylnorbornyl, 4-isopropylcyclohexyl,2,6,6-trimethylbicyclo[3.1.1]heptyl, and 3-methylcycloheptyl.

[0186] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, and R⁵ is selected from thegroup consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups.

[0187] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁹ is selectedfrom the group consisting of substituted and unsubstituted alkyl,arylalkyl, and heteroarylalkyl groups.

[0188] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituteddialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,3-methylbenzyl, benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,and thiophene groups.

[0189] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups.

[0190] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophenegroups.

[0191] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a substituted orunsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group.

[0192] In another embodiment, X, Y, L, Z¹, Z², Z³, R¹, R², and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a piperazino groupoptionally. substituted by one or two alkyl groups, for example, one ortwo methyl groups.

[0193] There has also been provided, in accordance with another aspectof the invention, a compound of formula II:

[0194] wherein

[0195] A is selected from the group consisting of C or CH;

[0196] X and Y are independently selected from the group consisting ofCH₂, N, C═O, C═S, (CR⁶R⁷)_(n), S═O, SO₂, O, NR⁹, S, C(═O)—(CR⁶R⁷)_(n),and C(═S)(CR⁶R⁷)_(n);

[0197] n is 1, 2, or 3;

[0198] W is selected from the group consisting of

[0199] Z¹, Z², and Z³ are independently selected from the groupconsisting of CR⁸ and N;

[0200] L is selected from the group consisting of N, O, S, S═O, SO₂,C(O), NC(O), NC(S), OC(O), OC(S), C(NR¹⁰), C(NOR¹⁰), and a covalentbond;

[0201] R¹ is selected from the group consisting of H, and substitutedand unsubstituted arylalkyl, heteroarylalkyl, aryl, heterocyclyl,cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, andalkyl groups;

[0202] R² is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, andarylalkyl groups;

[0203] R³ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, andcycloalkylalkyl groups, or R² and R³ may join together to form a ringcontaining at least two N atoms;

[0204] R⁴ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR² and R⁴ may join together to form a ring containing at least two Natoms;

[0205] R⁵ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl or heteroaryl group, or R³ andR⁵ may join together to form a ring containing at least two N atoms;

[0206] R⁶ and R⁷ may be the same or different, and are eachindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;

[0207] R⁸ is independently selected from the group consisting of H, Cl,I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy,amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; and

[0208] R⁹ and R¹⁰ are independently selected from the group consistingof H, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, alkylcarbonyl, and arylcarbonyl groups.

[0209] Compounds provided by the invention further include prodrugs ofthe compound of formula II, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, hydrates thereof, hydridesthereof, or solvates thereof.

[0210] In one embodiment, X is N, Y is NH, A is C, and the bond betweenX and A is a double bond.

[0211] In another embodiment, X is NH, Y is N, A is C, and the bondbetween Y and A is a double bond.

[0212] In another embodiment, A is C and the bond between either A and Xor between A and Y is a double bond.

[0213] In another embodiment, X, Y, and A have any of the values ofprevious embodiments, and L is a covalent bond.

[0214] In another embodiment, X, Y, A, and L have any of the values ofprevious embodiments, and Z¹, Z², and Z³ are all CH.

[0215] In another embodiment, X, Y, A, and L have any of the values ofprevious embodiments, and at least one of Z¹, Z², or Z³ is N.

[0216] In another embodiment, X, Y, A, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of substituted and unsubstituted arylalkyl, alkenyl,heteroarylalkyl, and heterocyclylalkyl groups.

[0217] In another embodiment, X, Y, A, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is 2,4-disubstituted phenethyl.

[0218] In another embodiment, X, Y, A, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of 2,4-dihalophenethyl, and 2,4-dialkylphenethyl.

[0219] In another embodiment, X, Y, A, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of phenethyl, 2,4-dichlorophenethyl, 4-methoxyphenethyl,4-bromophenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4-chlorobenzyl,4-ethylphenethyl, cyclohexenylethyl, 2-methoxyphenethyl,2-chlorophenethyl, 2-fluorophenethyl, 3-methoxyphenethyl,3-fluorophenethyl, thienylethyl, indolylethyl, 4-hydroxyphenethyl, and3,4-dimethoxyphenethyl.

[0220] In another embodiment, X, Y, A, L, Z¹, Z², Z³ and R¹, have any ofthe values of previous embodiments, and R² is H.

[0221] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups.

[0222] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cycloalkyl, alkenyl,alkyl, and aryl groups.

[0223] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cyclohexyl,2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl,2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl,3,4-dialkylcyclohexyl, 3-alkylcyclohexyl, 4-alkylcyclohexyl,3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, cyclopentyl, cycloheptyl, cyclohexenyl,isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl,2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl,adamantyl, isocamphenyl, carenyl, 7,7dialkylnorbornyl, bornyl,norbornyl, and decalinyl groups.

[0224] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cyclohexyl,2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl,2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl,3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,cyclohex-3-enyl, 3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl,2-methylcycloheptyl, cyclohexylmethyl, isopinocampheyl,7,7-dimethylnorbornyl, 4-isopropylcyclohexyl,2,6,6-trimethylbicyclo[3.1.1]heptyl, and 3-methylcycloheptyl.

[0225] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R², and R³have any of the values of previous embodiments, and R⁵ is selected fromthe group consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups.

[0226] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R²and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituted alkyl,arylalkyl, and heteroarylalkyl groups.

[0227] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituteddialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,3-methylbenzyl, benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,and thiophene groups.

[0228] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups.

[0229] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophenegroups.

[0230] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a substituted orunsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group.

[0231] In another embodiment, X, Y, A, L, Z¹, Z², Z³, R¹, R², and R³have any of the values of previous embodiments, and R⁴ and R⁵, togetherwith the nitrogen to which they are bound, form a piperazino groupoptionally substituted by one or two alkyl groups, for example, one ortwo methyl groups.

[0232] There has also been provided, in accordance with another aspectof the invention, a compound of formula III:

[0233] wherein

[0234] X and Y are independently selected from the group consisting ofCH₂, N, C═O, NR⁹, C═S, S═O, SO₂, O, S, (CR⁶R⁷)_(n), C(═O)—(CR⁶R⁷)_(n),and C(═S)—(CR⁶R⁷)_(n);

[0235] D is selected from the group consisting of N, and C;

[0236] If X is N, then Y is not N, but may be NH;

[0237] If Y is N, then X is not N, but may be NH;

[0238] If X is CH₂, then Y is not CH₂;

[0239] If Y is CH₂, then X is not CH₂;

[0240] If X is NH, then Y is not NH;

[0241] If Y is NH, then X is not NH;

[0242] L is selected from the group consisting of N, O, S, S═O, SO₂,C(O), NC(O), NC(S), OC(O), OC(S), C(NR¹⁰), C(NOR¹⁰), and a covalentbond;

[0243] W is selected from the group consisting of

[0244] Z¹, Z², and Z³ are independently selected from the groupconsisting of CR⁸ and N;

[0245] R¹ is selected from the group consisting of H, and substitutedand unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups;

[0246] R² is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, andarylalkyl groups;

[0247] R³ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, andcycloalkylalkyl groups, or R² and R³ may join together to form a ringcontaining at least two N atoms;

[0248] R⁴ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR² and R⁴ may join together to form a ring containing at least two Natoms;

[0249] R⁵ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl or heteroaryl group, or R³ andR⁵ may join together to form a ring containing at least two N atoms;

[0250] R⁶ and R⁷ may be the same or different, and are eachindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;

[0251] R⁸ is independently selected from the group consisting of H, Cl,I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy,amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; and

[0252] R⁹ and R¹⁰ are independently selected from the group consistingof H, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, alkylcarbonyl, and arylcarbonyl groups.

[0253] Compounds provided by the invention further include prodrugs ofthe compound of formula III, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, hydrates thereof, hydridesthereof, or solvates thereof.

[0254] In one embodiment, X is CH₂, Y is C═O, and D is N.

[0255] In another embodiment, X is C═O, Y is CH₂, and D is N.

[0256] In another embodiment, X is C═O, Y is C═O, and D is N.

[0257] In another embodiment, X is N, Y is NH, D is C, and the bondbetween X and D is a double bond.

[0258] In another embodiment, X is NH, Y is N, D is C, and the bondbetween Y and D is a double bond.

[0259] In another embodiment, X, Y, and D have any of the values ofprevious embodiments, and L is a covalent bond.

[0260] In another embodiment, X, Y, D, and L have any of the values ofprevious embodiments, and Z¹, Z², and Z³ are all CH.

[0261] In another embodiment, X, Y, D, and L have any of the values ofprevious embodiments, and at least one of Z¹, Z², or Z³ is N.

[0262] In another embodiment, X, Y, D, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of substituted and unsubstituted arylalkyl, alkenyl,heteroarylalkyl, and heterocyclylalkyl groups.

[0263] In another embodiment, X, Y, D, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is 2,4-disubstituted phenethyl.

[0264] In another embodiment, X, Y, D, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of 2,4-dihalophenethyl, and 2,4-dialkylphenethyl.

[0265] In another embodiment, X, Y, D, L, Z¹, Z², and Z³ have any of thevalues of previous embodiments, and R¹ is selected from the groupconsisting of phenethyl, 2,4-dichlorophenethyl, 4-methoxyphenethyl,4-bromophenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4-chlorobenzyl,4-ethylphenethyl, cyclohexenylethyl, 2-methoxyphenethyl,2-chlorophenethyl, 2-fluorophenethyl, 3-methoxyphenethyl,3-fluorophenethyl, thienylethyl, indolylethyl, 4-hydroxyphenethyl, and3,4-dimethoxyphenethyl.

[0266] In another embodiment, X, Y, D, L, Z¹, Z², Z³, and R¹ have any ofthe values of previous embodiments, and R² is H.

[0267] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups.

[0268] In another embodiment, X, Y, D, L, Z¹, Z³, R¹, and R² have any ofthe values of previous embodiments, and R³ is selected from the groupconsisting of substituted and unsubstituted cycloalkyl, alkenyl, alkyl,and aryl groups.

[0269] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cyclohexyl,2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl,2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl,3,4-dialkylcyclohexyl, 3-alkylcyclohexyl, 4-alkylcyclohexyl,3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, cyclopentyl, cycloheptyl, cyclohexenyl,isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl,2-arylalkylcyclohexyl, .2-benzylcyclohexyl, 4-phenylcyclohexyl,adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl,norbornyl, and decalinyl groups.

[0270] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, and R² haveany of the values of previous embodiments, and R³ is selected from thegroup consisting of substituted and unsubstituted cyclohexyl,2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl,2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl,3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,cyclohex-3-enyl, 3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl,2-methylcycloheptyl, cyclohexylmethyl, isopinocampheyl,7,7-dimethylnorbornyl, 4-isopropylcyclohexyl,2,6,6-trimethylbicyclo[3.1.1]heptyl, and 3-methylcycloheptyl.

[0271] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁵ is selected from thegroup consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heateroarylalkyl, and cycloalkylalkyl groups.

[0272] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, R⁴ is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituted alkyl,arylalkyl, and heteroarylalkyl groups.

[0273] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, R⁴is H, and R⁵ is selectedfrom the group consisting of substituted and unsubstituteddialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,3-methylbenzyl, benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,and thiophene groups.

[0274] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups.

[0275] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵ may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophenegroups.

[0276] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a substituted orunsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group.

[0277] In another embodiment, X, Y, D, L, Z¹, Z², Z³, R¹, R² and R³ haveany of the values of previous embodiments, and R⁴ and R⁵, together withthe nitrogen to which they are bound, form a piperazino group optionallysubstituted by one or two alkyl groups, for example, one or two methylgroups.

[0278] There has also been provided, in accordance with another aspectof the invention, a composition comprising a compound according to theinstant invention and a pharmaceutically acceptable carrier.

[0279] There has also been provided, in accordance with another aspectof the invention, a method of activating MC4-R, comprising administeringto a subject in need thereof, an effective amount of a compound orcomposition of the instant invention.

[0280] There has also been provided, in accordance with another aspectof the invention, a method of treating an MC4-R mediated disease,comprising administering to a subject in need thereof, a compound orcomposition of the instant invention.

[0281] In one embodiment, a disease to be treated by those methods ofthe instant invention is obesity, or type I or type II diabetes.

[0282] There has also been provided, in accordance with another aspectof the invention, a method of decreasing blood glucose levels,comprising administering to a subject in need thereof, a compound orcomposition of the instant invention.

[0283] In various alternative embodiments, the composition isadministered orally, rectally, by subcutaneous injection, by intravenousinjection, by intramuscular injection, or by intraperitoneal injection.

[0284] The variables “(CR⁶R⁷)_(n)”, “C(═O)—(CR⁶R⁷)_(n)”, and“C(═S)—(CR⁶R⁷)_(n)” are used with respect to X and Y in compounds offormula I, II, and III where n has the value of 1, 2, or 3. The variable“(CR⁶R⁷)_(n)” has the same meaning in compounds of formula I, II, andIII. The same is true with respect to the variables “C(═O)—(CR⁶R⁷)_(n)”and “C(═S)—(CR⁶R⁷)_(n)”. Compounds of formula I will be used toillustrate what these variables mean. In compounds of formula I as shownbelow

[0285] X and Y are independently selected from the group consisting ofCH₂, N, NH, C═O, C═S, S═O, SO₂, O, (CR⁶R⁷)_(n), C(═O)—(CR⁸R⁷)_(n), andC(═S)—{CR⁶R⁷)_(n); and n is 1, 2, or 3 as described above. The variable“(CR⁶R⁷)_(n)” indicates that X and/or Y may be a one, two, or threecarbon chain with the carbons bearing the R⁶ and R⁷groups. Thus, if X isa three carbon chain (n=3) and Y is a one carbon chain, the ring bearingthe X, Y and N will contain 7 members. It should be noted that where n=3and X or Y is a “(CR⁸R⁷)_(n)” group, the three carbon chain may besubstituted where each carbon bears the same R⁶ and R⁷ substituentsalthough this is not required. For example, X could be a—CH₂CH(Cl)C(Cl)₂— group because R⁶ and R⁷ may be H and Cl. Thus, thenomenclature used herein is not meant to restrict each of the carbons tobearing exactly the same substituents as would be the case for n=3 foran X group such as —CH(Cl)—CH(Cl)—CH(Cl)—. This same feature is truewith respect to the variables “C(═O)—(CR⁶R⁷)_(n)” and“C(═S)—(CR⁶R⁷)_(n)”. With respect to the variables “C(═O)—(CR⁶R⁷)_(n)”and “C(═S)—(CR⁶R⁷)_(n)”, X and/or Y may contain from two to four carbonatoms since n=1, 2, or 3, and the C═O and C═S groups of these speciescontains one carbon atoms. With respect to the variables“C(═O)—(CR⁶R⁷)_(n)” and “C(═S)—(CR⁶R⁷)_(n)”, either terminus of thegroup may be bonded to the N atom in the ring containing the X, Y, andN. Thus, the carbonyl carbon of the C(═O)—(CR⁶R⁷)_(n) group may be thecarbon directly bonded to the N in the ring, but one of the CR⁶R⁷carbons may alternatively be bonded to the ring N atom. Preferably,however, it is the C═O and C═S carbons of such groups that is bonded tothe ring N atoms.

[0286] As described above, in some embodiments L may be a covalent bond.In embodiments where L is a covalent bond, the R¹ group is directlybonded to the N in the ring containing the X and Y in compounds offormula I or is directly bonded to A or D in the ring containing the Xand Y in compounds of formulas II and III respectively.

[0287] Pharmaceutically acceptable salts include a salt with aninorganic base, organic base, inorganic acid, organic acid, or basic oracidic amino acid. As salts of inorganic bases, the invention includes,for example, alkali metals such as sodium or potassium, alkali earthmetals such as calcium and magnesium or aluminum, and ammonia. As saltsof organic bases, the invention includes, for example, trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine. As salts of inorganic acids, the instant inventionincludes, for example, hydrochloric acid, hydroboric acid, nitric acid,sulfuric acid, and phosphoric acid. As salts of organic acids, theinstant invention includes, for example, formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basicamino acids, the instant invention includes, for example, arginine,lysine and ornithine. Acidic amino acids include, for example, asparticacid and glutamic acid.

[0288] Prodrugs, as used in the context of the instant invention,includes those derivatives of the instant compounds which undergo invivo metabolic biotransformation, by enzymatic or nonenzymaticprocesses, such as hydrolysis, to form a compound of the invention.Prodrugs can be employed to improve pharmaceutical or biologicalproperties, as for example solubility, melting point, stability andrelated physicochemical properties, absorption, pharmacodynamics andother delivery-related properties.

[0289] The invention also includes tautomers of the instant compounds.For example, the instant invention also includes all tautomers offormula I, II, and III.

[0290] The instant invention also, therefore, includes prodrugs,pharmaceutically acceptable salts, stereoisomers, hydrates, hydrides, orsolvates of these tautomers.

[0291] The instant compounds may exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. In some cases, one stereoisomer may be moreactive and/or may exhibit beneficial effects in comparison to otherstereoisomers) or when separated from the other stereoisomers). However,it is well within the skill of the ordinary artisan to separate, and/orto selectively prepare said stereoisomers. Accordingly, “stereoisomers”of the instant invention necessarily includes mixtures of stereoisomers,individual stereoisomers, or optically active forms.

[0292] The instant invention also provides for compositions which may beprepared by mixing one or more compounds of the instant invention, orpharmaceutically acceptable salts or tautomers thereof, withpharmaceutically acceptable carriers, excipients, binders, diluents orthe like, to treat or ameliorate a variety of disorders. Examples ofsuch disorders include, but are not limited to obesity, erectiledisorders, cardiovascular disorders, neuronal injuries or disorders,,inflammation, fever, cognitive disorders, sexual behavior disorders. Atherapeutically effective dose further refers to that amount of one ormore compounds of the instant invention sufficient to result inamelioration of symptoms of the disorder. The pharmaceuticalcompositions of the instant invention can be manufactured by methodswell known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, emulsifying or levigatingprocesses, among others. The compositions can be in the form of, forexample, granules, powders, tablets, capsules, syrup, suppositories,injections, emulsions, elixirs, suspensions or solutions. The instantcompositions can be formulated for various routes of administration, forexample, by oral administration, by transmucosal administration, byrectal administration, or subcutaneous administration as well asintrathecal, intravenous, intramuscular, intraperitoneal, intranasal,intraocular or intraventricular injection. The compound or compounds ofthe instant invention can also be administered in a local rather than asystemic fashion, such as injection as a sustained release formulation.The following dosage forms are given by way of example and should not beconstrued as limiting the instant invention.

[0293] For oral, buccal, and sublingual administration, powders,suspensions, granules, tablets, pills, capsules, gelcaps, and capletsare acceptable as solid dosage forms. These can be prepared, forexample, by mixing one or more compounds of the instant invention, orpharmaceutically acceptable salts or tautomers thereof, with at leastone additive or excipient such as a starch or other additive. Suitableadditives or excipients are sucrose, lactose, cellulose sugar, mannitol,maltitol, dextran, sorbitol, starch, agar, alginates, chitins,chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens,casein, albumin, synthetic or semi-synthetic polymers or glycerides,methyl cellulose, hydroxypropylmethyl-cellulose, and/orpolyvinylpyrrolidone. Optionally, oral dosage forms can contain otheringredients to aid in administration, such as an inactive diluent, orlubricants such as magnesium stearate, or preservatives such as parabenor sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol orcysteine, a disintegrating agent, binders, a thickeners, buffers, asweeteners, flavoring agents or perfuming agents. Additionally,dyestuffs or pigments may be added for identification. Tablets and pillsmay be further treated with suitable coating materials known in the art.

[0294] Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions,slurries and solutions, which may contain an inactive diluent, such aswater. Pharmaceutical formulations may be prepared as liquid suspensionsor solutions using a sterile liquid, such as, but not limited to, anoil, water, an alcohol, and combinations of these. Pharmaceuticallysuitable surfactants, suspending agents, emulsifying agents, may beadded for oral or parenteral administration.

[0295] As noted above, suspensions may include oils. Such oils include,but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oiland olive oil. Suspension preparation may also contain esters of fattyacids such as ethyl oleate, isopropyl myristate, fatty acid glyceridesand acetylated fatty acid glycerides. Suspension formulations mayinclude alcohols, such as, but not limited to, ethanol, isopropylalcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, suchas but not limited to, poly(ethyleneglycol), petroleum hydrocarbons suchas mineral oil and petrolatum; and water may also be used in suspensionformulations.

[0296] For nasal administration, the pharmaceutical formulations may bea spray or aerosol containing and appropriate solvents and optionallyother compounds such as, but not limited to, stabilizers, antimicrobialagents, antioxidants, pH modifiers, surfactants, bioavailabilitymodifiers and combinations of these. A propellant for an aerosolformulation may include compressed air, nitrogen, carbon dioxide, or ahydrocarbon based low boiling solvent. The compound or compounds of theinstant invention are conveniently delivered in the form of an aerosolspray presentation from a nebulizer or the like.

[0297] Injectable dosage forms generally include aqueous suspensions oroil suspensions which may be prepared using a suitable dispersant orwetting agent and a suspending agent. Injectable forms may be insolution phase or in the form of a suspension, which is prepared with asolvent or diluent. Acceptable solvents or vehicles include sterilizedwater, Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils may be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[0298] For injection, the pharmaceutical formulation may be a powdersuitable for reconstitution with an appropriate solution as describedabove. Examples of these include, but are not limited to, freeze dried,rotary dried or spray dried powders, amorphous powders, granules,precipitates, or particulates. For injection, the formulations mayoptionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these. The compounds maybe formulated for parenteral administration by injection such as bybolus injection or continuous infusion. A unit dosage form for injectionmay be in ampoules or in multi-dose containers.

[0299] For rectal administration, the pharmaceutical formulations may bein the form of a suppository, an ointment, an enema, a tablet or a creamfor release of compound in the intestines, sigmoid flexure and/orrectum. Rectal suppositories are prepared by mixing one or morecompounds of the instant invention, or pharmaceutically acceptable saltsor tautomers of the compound, with acceptable vehicles, for example,cocoa butter or polyethylene glycol, which is present in a solid phaseat normal storing temperatures, and present in a liquid phase at thosetemperatures suitable to release a drug inside the body, such as in therectum. Oils may also be employed in the preparation of formulations ofthe soft gelatin type and suppositories. Water, saline, aqueous dextroseand related sugar solutions, and glycerols may be employed in thepreparation of suspension formulations which may also contain suspendingagents such as pectins, carbomers, methyl cellulose, hydroxypropylcellulose or carboxymethyl cellulose, as well as buffers andpreservatives.

[0300] Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991),which is incorporated herein by reference.

[0301] The formulations of the invention may be designed for to beshort-acting, fast-releasing, long-acting, and sustained-releasing asdescribed below. Thus, the pharmaceutical formulations may also beformulated for controlled release or for slow release.

[0302] The instant compositions may also comprise, for example, micellesor liposomes, or some other encapsulated form, or may be administered inan extended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations may be compressedinto pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants may employ known inert materials such as silicones andbiodegradable polymers.

[0303] A therapeutically effective dose refers to that amount of thecompound that results in amelioration of symptoms. Specific dosages maybe adjusted depending on conditions of disease, the age, body weight,general health conditions, sex, diet of the subject, dose intervals,administration routes, excretion rate, and combinations of drugs. Any ofthe above dosage forms containing effective amounts are well within thebounds of routine experimentation and therefore, well within the scopeof the instant invention. A therapeutically effective dose may varydepending upon the route of administration and dosage form. Thepreferred compound or compounds of the instant invention is aformulation that exhibits a high therapeutic index. The therapeuticindex is the dose ratio between toxic and therapeutic effects which canbe expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the doselethal to 50% of the population and the ED₅₀ is the dose therapeuticallyeffective in 50% of the population. The LD₅₀ and ED₅₀ are determined bystandard pharmaceutical procedures in animal cell cultures orexperimental animals.

[0304] The present invention also provides methods of enhancing MC4Ractivity in a human or non-human animal. The method comprisesadministering an effective amount of a compound, or composition, of theinstant invention to said mammal or non-human animal. Effective amountsof the compounds of the instant invention include those amounts thatactivate MC4-R which are detectable, for example, by an assay describedbelow in the illustrative Examples, or any other assay known by thoseskilled in the art that a detect signal transduction, in a biochemicalpathway, through activation of G-protein coupled receptors, for example,by measuring an elevated cAMP level as compared to a control model.Accordingly, “activating” means the ability of a compound to initiate adetectable signal. Effective amounts may also include those amountswhich alleviate symptoms of a MC4-R disorder treatable by activatingMC4R.

[0305] An MC4-R disorder, or MC4-R-mediated disease, which may betreated by those methods provided, include any biological disorder ordisease in which MC4-R is implicated, or which inhibition of MC4-Rpotentiates a biochemical pathway that is defective in the disorder ordisease state. Examples of such diseases are obesity, erectiledisorders, cardiovascular disorders, neuronal injuries or disorders,inflammation, fever, cognitive disorders, and sexual behavior disorders.In a preferred embodiment, the instant invention provides compounds,compositions, and methods effective for reducing energy intake and bodyweight; reducing serum insulin and glucose levels; alleviating insulinresistance; and reducing serum levels of free fatty acids. Accordingly,the instant invention is particularly effective in treating thosedisorders or diseases associated with obesity or type II diabetes.

[0306] “Treating” within the context of the instant invention,therefore, means an alleviation of symptoms associated with a disorderor disease, or halt of further progression or worsening of thosesymptoms, or prevention or prophylaxis of the disease or disorder. Forexample, within the context of obesity, successful treatment may includean alleviation of symptoms or halting the progression of the disease, asmeasured by reduction in body weight, or a reduction in amount of foodor energy intake. In this same vein, successful treatment of type I ortype II diabetes may include an alleviation of symptoms or halting theprogression of the disease, as measured by a decrease in serum glucoseor insulin levels in, for example, hyperinsulinemic or hyperglycemicpatents.

Compound Preparation

[0307] Many of the described specific synthetic transformation steps arefamiliar to those skilled in the art and their procedures are eitherdescribed or referenced in common texts such as in March AdvancedOrganic Chemistry 3^(rd) ed. (Wiley, 1985), Carey and Sundberg AdvancedOrganic Chemistry A and B 3^(rd) ed. (Plenum Press, 1990), and Vogel'sTextbook of Practical Organic Chemistry 5^(th) ed. (Longman, 1989).Implicit in the synthetic transformations are various techniques forpurification such as silica gel chromatography, crystallizations, anddistillations. These steps may be necessary for isolating the desiredproduct, regioisomer, enantiomer, or diastereomer from a reactionproduct mixture. Multistep syntheses may also involve the use ofprotecting groups to address issues of chemo and regioselectivity thatcannot otherwise be satisfactorily resolved with respect to chemicalpurity or yield.

[0308] The use of protecting groups in organic synthesis is well knownwith respect to various groups such as hydroxyl groups, amine groups,and sulfhydryl groups. These and other functionalities may be protectedfrom undesirable reactions with various protecting groups known to thoseskilled in the art such as those set forth in Protective Groups inOrganic Synthesis, Greene, T. W., John Wiley & Sons, New York, N.Y.,(1^(st) Edition, 1981) which can be added or removed using theprocedures set forth therein. Examples of protected hydroxyl groupsinclude, but are not limited to, silyl ethers such as those obtained byreaction of a hydroxyl group with a reagent such as, but not limited to,t-butyldimethyl-chlorosilane, trimethylchlorosilane,triisopropylchlorosilane, triethylchlorosilane; substituted methyl andethyl ethers such as, but not limited to methoxymethyl ether,methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether,2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethylether, allyl ether, benzyl ether; esters such as, but not limited to,benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.Examples of protected amine groups include, but are not limited to,amides such as, formamide, acetamide, trifluoroacetamide, and benzamide;imides, such as phthalimide, and dithiosuccinimide; and others. Examplesof protected sulfhydryl groups include, but are not limited to,thioethers such as S-benzyl thioether, and S4-picolyl thioether;substituted S-methyl derivatives such as hemithio, dithio and aminothioacetals; and others.

[0309] FIG. 1 illustrates a general synthetic route for compoundscontaining the following core structure:

[0310] In the first part of the synthesis the non-guanidino linkedportion of the bicyclic core is functionalized. In one embodiment of themethod of the invention, the condensation of an amine and an anhydridegives an N-substituted phthalimide. Alternatively, if a phthalimide isused as the starting material, the phthalimide nitrogen may befunctionalized by displacement of an activated alcohol. Thesetransformations allow access to a wide range of N-substitutedintermediates by varying the type of R₁OH or R₁NH₂ inputs. It canfurther be appreciated that use of the appropriate starting materialsfor the bicyclic core can also provide, for example, compounds of theinvention containing a nitrogen atom in the aromatic ring to which theguanidino moiety is attached.

[0311] In the next phase of the synthetic route, the functionalizedimide may be reduced to the lactam via a two step process. Afterseparation of the desired lactam regioisomer, the primary amine may beactivated by treatment with thiophosgene to form the thiotsocyanate.Sequential coupling of two amines yields the desired lactam products,which can exist in two tautomeric forms. One skilled in the art wouldrecognize that alternative couplings of amines to thioureas exist, suchas the use of a myriad of carbodiimide based coupling reagents oralkylation of the sulfur atom with an alkyl halide prior to addition ofan amine.

[0312] Use of the other regioisomer obtained from the reduction stepwould lead to the regioisomeric lactam and its tautomer shown in FIG. 2below.

[0313] Furthermore, the reduction steps in FIG. 1 can be omitted in itsentirety and the reaction scheme can be carried through to give theguanidino imide and its tautomer shown in FIG. 3 as products.Conversely, both carbonyl groups can be fully reduced to give thetetrahydro analogs.

[0314] Additional structural variations within the non-guanidino linkedportion of the bicyclic core itself can be achieved by starting with,for example, bicyclic lactams or bicyclic cycloamido compounds. Thesescaffolds can be generally be functionalized by methods known in the artsuch as N-alkylation with a variety of electrophiles (see R. Larock,Comprehensive Organic Transformations; VHC Pubiisher's Inc., 1989).Bicyclic lactams can also be generally functionalized as shown in FIG.4. An amine or its activated. equivalent (for example an alkyl aluminumamide) is first coupled with a lactone. The resulting product is thenused in a subsequent cyclodehydration reaction (for example a Mitsunobureaction) to give the functionalized bicyclic core. The guanidino moietymay then be installed as described above.

[0315] FIG. 5 illustrates a general synthetic route for compounds of theinvention containing the benzimidazole core structure. An activated acidis first condensed with a diaminonitrophenyl starting material followedby exposure of the resulting product to acidic conditions to provide thebenzimidazole core. The nitro moiety is then reduced and converted tothe functionalized quanidino substituent as described above.

[0316] In another embodiment of the invention, benzoxazole andbenzthiazole comprise the bicyclic core. These compounds may beconstructed as shown in FIG. 6. Commercially available (Aldrich)6-nitrobenzothiazole may be treated with base and quenched withN-chlorosuccinimide to give the halogenated intermediate. This compoundmay then be used in a number of metal mediated coupling reactions (forexample Heck, Stille, Sonogashira coupling reactions) to functionalizethe bicyclic core. The nitro group then serves as the attachment pointfor the guanidino unit.

[0317] The present invention, thus generally described, will beunderstood more readily by reference to the following examples, whichare provided by way of illustration and are not intended to be limitingof the present invention.

EXAMPLES

[0318] Compounds were named using the ACD/Name v. 4.53.

[0319] The following abbreviations are used throughout the Examples: eqequivalent DIAD diisopropylazodicarboxylate DIBAL-H diisobutlyaluminumhydride EDC 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimidehydrochloride EtOAc ethylacetate THF tetrahydrofuran TFA trifluoroaceticacid

Analytical Methodology

[0320] HPLC System:

[0321] HPLC was run on a Waters 2690 HPLC system.

[0322] column=Reliasil 50×4.6 mm (5 μm pore size)

[0323] method: (note: all solvents include 0.1% TFA) time flow rate(minutes) (mL/min) % water % CAN init. 2 95 5 15   2 20 80 15.5 2 0 10017.5 2 0 100 18.5 2 95 5

[0324] Model HPLC=(Waters 2690 Separations Module)

[0325] detector=(Waters 996 photodiode array detector)

[0326] LCMS were run on HP Senes 1100 LCMS system

[0327] HP LCMS (1100 series)

[0328] HP MSD (1100 series) time flow rate (minutes) (mL/min) % A* % B*0 0.8 95 5 .2 0.8 95 5 3.7 0.8 5 95 3.85 0.8 95 5 5 0.8 95 5

[0329] column=(brand=Eclipse XDB) 50×2 mm (5 μm) (C18)

[0330] MS Methodology

[0331] MWT: 150-800

[0332] CV: 20

[0333] Ionization: ESP+

[0334] i. Data: Centroid

[0335] Repeat: 1

[0336] Scan Time: 2 seconds

Example 1 Preparation of(3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0337] Step 1.

[0338] Preparation of2-[2-(2,4-dichlorophenyl)ethyl]-5-nitro-1H-isoindole-1,3(2H)-dione

[0339] 2-(2,4-dichlorophenyl)ethanamine was suspended in toluene with4nitrophthalic anhydride (1 eq) and heated to 150° C. After 2 hours, thereaction was cooled and checked for completion by LC/MS. The solvent wasthen removed in vacuo and the resulting product was taken on to the nextstep without further purification. R_(t) 3.36 minutes (HP LCMS), LC/MSm/z 365.1 (MH+).

[0340] Step 2.

[0341] Preparation of5-amino-2-[2-(2,4-dichlorophenyl)ethyl]-1H-isoindole-1,3(2H)-dione

[0342] The product of the previous step was taken up in ethanol (ormethanol) and purged with dry nitrogen. To this solution was introducedactivated Pd/C (10% w/w, 0.1 eq) and the mixture was hydrogenated forabout 30 minutes or until complete by LC/MS. The mixture was thenfiltered through celite, concentrated in vacuo, and taken on to the nextstep. R_(t) 2.95 minutes (HP LCMS), LC/MS m/z 335.0 (MH+).

[0343] Step 3.

[0344] Preparation of5-amino-2-[2-(2,4-dichlorophenyl)ethyl]-3-hydroxyisoindolin-1-one

[0345] To a CH₂Cl₂ solution of the phthalimide was added dropwiseDIBAL-H (3 eq, 1.0 M solution in CH₂Cl₂) at room temperature with goodstirring. After stirring for one hour, the reaction was diluted withether, NaF (12 eq), and distilled water (9 eq) and stirred for anadditional hour. The reaction mixture was then filtered through celiteto remove the aluminum precipitants. After washing the celite withadditional CH₂Cl₂, the filtrate was then concentrated in vacuo to give acrude product (mixture of regioisomers) was then used in the followingstep without further purification. R_(t) 2.09 minutes (HP LCMS) and 2.23minutes (HP LCMS), LC/MS m/z 337.2 (MH+).

[0346] Step 4.

[0347] Preparation of5-amino-2-[2-(2,4-dichlorophenyl)ethyl]isoindolin-1-one

[0348] To a CH₂Cl₂ (0.1 M solution) of the crude product from theprevious step was added dropwise triflouroacetic acid (6.0 eq) followedimmediately by dropwise addition of triethylsilane (2.9 eq). Afterstirring for an additional 15 minutes, the mixture was concentrated invacuo. The crude product of two regioisomeric lactams was then dissolvedin acetonitrile and purified via reverse phase (Cl8) prep HPLC. Thefractions for the desired regioisomeric lactam product (later retentiontime) were collected, frozen, and lyophilized. R_(t) 7.24minutes, LC/MSm/z 321.1 (MH+).

[0349] Step 5.

[0350] Preparation of2-[2-(2,4-dichlorophenyl)ethyl]-5-isothiocyanato-isoindolin-1-one

[0351] To a 0.5 M solution of the amine in acetone (0° C. ice bath) wasadded thiophosgene (3 eq) dropwise. After 30 minutes, the reactionmixture was allowed to warm to room temperature. After two hours, thereaction mixture was concentrated in vacuo to remove solvent and excessthiophosgene. The crude isothiocyanate product was then used in the nextstep without further purification. R_(t) 3.43 minutes (HP LCMS), LC/MSm/z 363.1 (MH+).

[0352] Step 6.

[0353] Preparation ofN-{2-[2-(2,4-dichlorophenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo(3.1.1]hept-3-yl]thiourea

[0354] To a solution of the crude isothiocyanate in dry acetonitrile(0.5.M solution) was added (+)-isopinocampheyl amine (1.5 eq). Afterstirring overnight, the reaction mixture was concentrated in vacuo andthe thiourea product was dissolved in CH₂Cl₂ and purified via flashchromatography (1:1 Hexanes:EtOAc). Fractions containing the thioureaproduct were concentrated in vacuo and dried to yield a creamish whitecolored solid. R_(t) 14.53 minutes, LC/MS m/z 516.4 (MH+).

[0355] Step 7.

[0356] Preparation of(3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0357] To a solution of the thiourea in THF (dry, 0.5 M) in a dry vialwas added (S)-(+)-2-methylpiperazine (3 eq) and EDC (3 eq). The vial wascapped tightly and heated to 80° C. for approximately 2 hours. Themixture was then allowed to cool to room temperature and concentrated invacuo. The reaction mixture was dissolved in DMSO along with TFA (1 eq)and purified by prep HPLC. The pure fractions were collected, frozen,and dried via lyopholization to give the product as a white solid. R_(t)8.36 minutes, LC/MS m/z 582.5 (MH+).

Example 2 Preparation of(3S)-N-[2-[2-(2,4-dichlorophenyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0358] Step 1.

[0359] Preparation of2-[2-(2,4-dichlorophenyl)ethyl]-5-nitro-1H-isoindole-1,3(2H)-dione

[0360] 2-(2,4-dichlorophenyl)ethanamine was suspended in toluene with4-nitrophthalic anhydride (1 eq) and heated to 150° C. After 2 hours,the reaction was cooled and checked for completion by LC/MS. The solventwas then removed in vacuo and the resulting product was taken on to thenext step without further purification. R_(t) 3.9.1 minutes, LC/MS m/z365.1 (MH+).

[0361] Step 2.

[0362] Preparation of5-amino-2-[2-(2,4-dichlorophenyl)ethyl]-1H-isoindole-1,3(2H)-dione

[0363] The product of the previous step was taken up in ethanol (ormethanol) and purged with dry nitrogen. To this solution was introducedactivated Pd/C (10% w/w₇ 0.1 eq) and the mixture was hydrogenated forabout 30 minutes or until complete by LC/MS. The mixture was thenfiltered through celite, concentrated in vacuo, and taken on to the nextstep. R_(t) 2.96 minutes (HP LCMS), LC/MS m/z 335.1 (MH+).

[0364] Step 3.

[0365] Preparation of2-[2-(2,4-dichlorophenyl)ethyl]-5-isothiocyanatoiso-1H-isoindole-1,3(2H)dione

[0366] To a 0.5 M solution of the amine in acetone (0° C. ice bath) wasadded thiophosgene (3 eq) dropwise. After 30 minutes, the reactionmixture was allowed to warm to room temperature. After two hours, thereaction mixture was concentrated in vacuo to remove solvent and excessthiophosgene. The crude isothiocyanate product was then used in the nextstep without further purification. R_(t) 3.75 minutes (HP LCMS), LC/MSm/z 377.0 (MH+).

[0367] Step 4.

[0368] Preparation ofN-{2-[2-(2,4-dichlorophenyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]thiourea

[0369] To a solution of the crude isothiocyanate in dry acetonitrile(0.5 M solution) was added (+)-isopinocampheyl amine (1.5 eq). Afterstirring overnight, the reaction mixture was concentrated i n vacuo andthe thiourea product was dissolved in CH₂Cl₂ and purified via flashchromatography (1:1 Hexanes:EtOAc). Fractions containing the thioureaproduct were concentrated in vacuo and dried overnight vialyophilization to yield a yellowish-brown solid. R_(t) 3.98 minutes (HPLCMS), LC/MS m/z 596.1 (MH+).

[0370] Step 5.

[0371] Preparation of(3S)-N{2-[2-(2,4-dichlorophenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0372] To a solution of the thiourea in THF (dry, 0.5 M) in a dry vialwas added (S)-(+)-2-methylpiperazine (3 eq) and EDC (3 eq). The vial wascapped tightly and heated to 80° C. for approximately 2 hours. Themixture was then allowed to cool to room temperature and concentrated invacuo. The reaction mixture was dissolved in DMSO along with TFA (1 eq)and purified by prep HPLC. The pure fractions were collected, frozen,and dried via lyopholization to give the product as a white solid. R_(t)9.57 minutes, LC/MS m/z 596.3 (MH+).

[0373] Examples 3-16 were prepared using the procedures described for 1and 2.

Example 3(3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0374] Synthesized from 2-(2,4-dichlorophenyl)ethanamine. R_(t) 8.72minutes, LC/MS m/z 582.5 (MH+).

Example 4 (3S)-N-[2-(2,4dichlorobenzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0375] Synthesized from 1-(2,4-dichlorophenyl)methanamine. R_(t) 8.72minutes, LC/MS m/z 582.5 (MH+).

Example 5(3S)N-{2-[(1S)-1-benzyl-2-hydroxyethyl[-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0376] Synthesized from L-phenylalaninol. R_(t) 7.56 minutes, LC/MS m/z558.7 (MH+).

Example 6(3S)-N-{2-[(1R)-1-benzyl-2-hydroxyethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0377] Synthesized from D-phenylalaninol. R_(t) 7.52 minutes, LC/MS m/z558.7 (MH+).

Example 7(3S)-N-{2-[2-(2-fluoro-4-methylphenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0378] Synthesized from 2-(3-fluoro-5-methylphenyl)ethanamine. R_(t) 7.8minutes, LC/MS m/z 546.2 (MH+).

Example 8(3S)-N-{2-[(1S)-1-(2,4-dichlorobenzyl)-2-hydroxyethyl]-1,3dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0379] Synthesized from L-2,4-dichlorophenylalaninol, obtained in onestep from the reduction of L-2,4-dichlorophenylalanine (see, forexample, JOC 2000, 65, 5037-5042). R_(t) 8.46 minutes, LC/MS m/z 626.2(MH+).

Example 9(3S)-N-{2-[(1S)-1-(2,4-dichlorobenzyl)-2-hydroxyethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0380] Synthesized from L-2,4-dichlorophenylalaninol, obtained in onestep from the reduction of L-2,4-dichlorophenylalanine (see, forexample, JOC 2000, 65, 5037-5042). R_(t) 7.71 minutes, LC/MS m/z 612.2(MH+).

Example 10(3S)-N-{2-[2-(2-fluoro-4-methoxyphenyl)ethyl]-1,3dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0381] Synthesized from 2-(2-fluoromethoxyphenyl)ethanamine. R_(t) 8.4minutes, LC/MS , m/z 576.2 (MH+).

Example 11(3S)-N-{2-[2-(2,4-difluorophenyl)ethyl-1,3-dioxo-2,3dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo(3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0382] Synthesized from 2-(2,4-difluorophenyl)ethanamine. R_(t) 8.53minutes, LC/MS m/z 564.2 (MH+).

Example 12(3S)-N-{2-[2-(2,4-dimethoxyphenyl)ethyl]-1,3-dioxo-2,3dihydro-1H-isoindol-5-yl}-3-methyl-N′-(1S,2S,3S,5R)-2,6,6-trimethylbicyclo3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0383] Synthesized from 2-(2,4-dimethoxyphenyl)ethanamine. R_(t) 8.51minutes, LC/MS m/z 588.3 (MH+).

Example 13(3S)-N-{2-[2-(2,4dimethylphenyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0384] Synthesized from 2-(2,4-dimethylphenyl)ethanamine. R_(t) 9.43minutes, LC/MS m/z 556.2 (MH+).

Example 14(3S)-N-{2-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0385] Synthesized from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol,R_(t) 8.68 minutes, LC/MS m/z 574.3 (MH+).

Example 15 (3S)-N-{2-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0386] Synthesized from (1R,2R)-(−)-2-amino-1-phenyl-1,3-propanediol.R_(t) 6.64 minutes, LC/MS m/z 574.3 (MH+).

Example 16(3S)-N-{2-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0387] Synthesized from (1 R,2S)-(+)-2-amino-1-phenyl-1,3-propanediol.R_(t) 6.63 minutes, LC/MS m/z 574.3 (MH+).

Example 17(3S)-N-{2-[2-(2-fluoro-4-methoxyphenyl)ethyl]-1oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0388] Synthesized from 2-(2-fluoro-4-methoxyphenyl)ethanamine. R_(t)7.42 minutes, LC/MS m/z 562 (MH+).

Example 18(3S)-N-{2-[2-(2,4-difluorophenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0389] Synthesized from 2-(2,4-difluorophenyl)ethanamine. R_(t) 7.5minutes, LC/MS m/z 550 (MH+).

Example 19(3S)-N-{2-[2-(2,4-difluorophenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0390] Synthesized from 2-(2,4-difluorophenyl)ethanamine. R_(t) 7.82minutes, LC/MS m/z 550 (MH+).

Example 20(3S)-N-{2-[2-(2,4-dimethylphenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0391] Synthesized from 2-(2,4-dimethylphenyl)ethanamine. R_(t) 8.21minutes, LC/MS m/z 542.1 (MH+).

Example 21(3S)-N42-[2-(2,4-dimethylphenyl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0392] Synthesized from 2-(2,4dimethylphenyl)ethanamine. R_(t) 8.5minutes, LC/MS m/z 542.1 (MH+).

Example 22(3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-3-methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0393] 6-nitroisochroman-1-one was treated with the dimethylaluminumamide prepared from 2-(2,4-dichlorophenyl)ethanamine, and the productobtained was cyclized using Mitsunobu conditions (as in Ian. Bell et al,Tetrahedron. Lett. (2000),41, 1141-1145). The nitro group was thenreduced, and the amine was converted to the substituted guanidine (as insteps 2-5 of Example 2 above) to give the title compound. R_(t) 9.06minutes, LC/MS m/z 596.1 (MH+).

Example 23(3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl]-1H-benzimidazol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0394] 2,4-dichlorophenyl propionic acid (1.0 eq) was mixed with4-nitro-1,2-phenylenediamine (1.1 eq) and EDC (1.5 eq) in THF at roomtemperature for 8 hours. The solution was diluted with ethyl acetate andwashed with water (3×). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. The product wasthen subjected to refluxing glacial acetic acid for 30 minutes. Afterremoval of the acetic acid in vacuo, the residue was free-based withsodium carbonate. The resulting compound was then subjected to thehydrogenation and guanidino functionalization conditions described inExample 2 above (steps 2, 3, 4, and 5) to give the desired product.R_(t) 7.08 minutes, LC/MS m/z 567.2 (MH+).

[0395] Examples 24 and 25 can be prepared using the procedures describedfor Example 23.

Example 24 (3S)-N-{2-[2-(2,4-dimethylphenyl)ethyl]-1H-benzimidazol-6-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1hept-3-yl]piperazine-1-carboximidamide

[0396] Synthesized from 3-(2,4-dimethylphenyl)propanoic acid. R_(t) 6.93minutes, LC/MS m/z 527.3 (MH+).

Example 25 (3S)-N-{2-[2-(2-chloro-4-fluorophenyl)ethyl]-1H-benzimidazol-6-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

[0397] Synthesized from 3-(2-chloro-4-fluorophenyl)propanoic acid. R_(t)6.54 minutes, LC/MS m/z 551.4 (MH+).

[0398] In addition to the synthesis described above, many of thesynthetic transformations presented in U.S. Provisional Application No.60/245,579 are relevant to the synthesis of the compounds of the presentinvention. Thus, U.S. Provisional Application No. 60/245,579, filed Nov.6, 2000 is hereby incorporated by reference in its entirety.

In Vitro Data

[0399] EC₅₀ values of test compounds were determined by treating cellsexpressing MC4-R with test compound and lysing the cells and measuringintercellular cAMP concentration with an Amersham-Pharmacia RPA-559 cAMPScintillation Proximity Assay (SPA) kit. The following compounds weresynthesized and tested according to this assay. The following compoundsare merely illustrative and should not be construed as limiting of theinstant invention. Compounds having an in vitro potency (as measured byEC₅₀ value) of less than 3 μM include:

[0400](3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo3.1.1]hept-3-yl]piperazine-1carboximidamide;(3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl]-3-oxo-2,3-dihydra-1H-isoindol-5yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-[2-(2,4-dichlorobenzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[(1S)-1-benzyl-2-hydroxyethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[(1R)-1-benzyl-2-hydroxyethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2-fluoro-4-methylphenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[(1S)-1-(2,4-dichlorobenzyl)-2-hydroxyethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2-fluoro-4-methoxyphenyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-difluorophenyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-methoxyphenyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-dimethylphenyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2-fluoromethoxyphenyl)ethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-difluorophenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-difluorophenyl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[1S,2S,3S,5R)-2,6,6-trimethylbicyclo-3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-dimethylphenyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-dimethylphenyl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}-3-methyl-N′-[1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl]-1H-benzimidazol-5-yl}3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-dimethylphenyl)ethyl]-1H-benzimidazol-6-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[2-(2,4-dichlorophenyl)ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl}-3-methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo(3.1.1]hept-3-yl]piperazine-1-carboximidamide;(3S)-N-{2-[(1S)-1-(2,4-dichlorobenzyl)-2-hydroxyethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximidamide;and(3S)-N-{2-[2-(2-chloro-4-fluorophenyl)ethyl]-1H-benzimidazol-6-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide.

In Vivo Studies of MC4-R Agonists on Energy Intake, Body Weight,Hyperinsulinemia, and Glucose Levels.

[0401] In vivo studies are conducted to observe the effect of MCR-4agonists on energy intake, body weight, hyperinsulinemia, and glucoselevels. All studies are conducted with male 9-10 week old ob/ob micewhich display early onset of obesity, insulin resistance and diabetesdue to leptin deficiency. Mice are acclimated in the facility for 1 weekbefore studies and are caged individually. Vehicle-treated (control) anddrug treated mice studies are always run in parallel. In multi-daystudies, mice (8-15 per group) are monitored for baseline body weight,fasting levels of glucose, insulin, blood lipids and energy expenditureand then are injected twice daily (9 a.m. and 5 p.m.) with 3 mg/kg of anMC4-R agonist according to the invention for 2-4 weeks. Body weight aswell as food and water intake are monitored daily. Animals are fastedovernight for measurements of fasting levels of glucose, insulin, andlipids once a week until the end of the study. Energy expenditure(resting metabolic rate, i.e., O₂ consumption and CO₂ production) aremonitored in air tight chambers at the end of the study on fed animals.O₂ consumption and CO₂ production are measured using Oxymax systems(Columbus Instruments). Oral glucose tolerance test (OGTT—a routine testfor diabetes and glucose intolerance) is performed on overnight fastedmice at the end of the study. Blood glucose and oral glucose toleranceare measured using a glucose monitor (Onetouch sold by Lifescan). Freefatty acids are measured using an nonesterfifed free fatty acidsenzymatic assay (Waco Chemicals). Serum Insulin levels are measured byimmunoassay (Alpco).

[0402] The results of the above studies show that a significantreduction in food intake occurs in those mice treated IP with thecompounds of the present invention. The results also show that micetreated with the compounds of the present invention show a significantbody weight reduction compared to mice not treated with the compounds ofthe present invention. Vehicle treated mice show an increase in bloodglucose consistent with the rapid progression of diabetes in this mousestrain, whereas the onset of diabetes is slowed down in mice treatedwith the compounds of the present invention. Oral glucose tolerancetests are performed. Orally administered glucose quickly elevates bloodglucose similar to after eating a meal. Vehicle treated mice show anelevated response to glucose consistent with their diabetic state,whereas mice treated with the compounds of the present invention show avery much

glucose disposal. Mice are fasted overnight and free fatty acid levelsare measured the following morning. Vehicle treated mice show elevatedfree fatty acid levels consistent with their obese state, whereas micetreated with the compounds of the present invention show a dramatic 50%decrease. Serum insulin levels are measured one hour after since IPdosing of compounds of the present invention in overnight fasted ob/obmice. Mice treated with the compounds of the present invention show adose dependent decrease relative to vehicle.

1. A compound of formula I

wherein X and Y are independently selected from the group consisting ofCH₂, N, NR⁹, C—O, C═S, S═O, SO₂, S, O, (CR⁶R⁷)_(n), C(═O)—(CR⁶R⁷)_(n),and C(═S)—(CR⁶R⁷)_(n); n is 1, 2, or 3; W is selected from the groupconsisting of

L is selected from the group consisting of N, O, S, S═O, SO₂, C(O),NC(O), NC(S), OC(O), OC(S), C(NR¹⁰), C(NOR¹⁰), and a covalent bond; Z¹,Z², and Z³ are independently selected from the group consisting of CR⁸and N; R¹ is selected from the group consisting of substituted andunsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups; R² is selected from the group consisting ofH, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkylalkyl, aryl, and arylalkyl groups; R³ is selected from thegroup consisting of H, and substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, or R² and R³ mayjoin together to form a ring containing at least two N atoms; R⁴ isselected from the group consisting of H, and substituted andunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR² and R⁴ may join together to form a ring containing at least two Natoms; R⁵ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl or heteroaryl group, or R³ andR⁵ may join together to form a ring containing at least two N atoms; R⁶and R⁷ may be the same or different, and are each independently selectedfrom the group consisting of H, Cl, I, F, Br, OH, NH₂, CN, NO₂, andsubstituted and unsubstituted alkoxy, amino, alkyl, alkenyl, alkynyl,alkylamino, dialkylamino, cycloalkyl, heterocyclylamino,heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; R⁸ isindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; R⁹ andR₁₀ are independently selected from the group consisting of H, andsubstituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,alkylcarbonyl, and arylcarbonyl groups; and prodrugs thereof,pharmaceutically acceptable salts thereof, stereoisomers thereof,tautomers thereof, hydrates thereof, hydrides thereof, or solvatesthereof.
 2. A compound of formula II

wherein A is selected from the group consisting of C or CH; X and Y areindependently selected from the group consisting of CH₂, N, C═O, C═S,(CR⁶R⁷)_(n), S═O, SO₂, O, NR⁹, S, C(═O)—(CR⁶R⁷)_(n), andC(═S)—(CR⁶R⁷)_(n); n is 1, 2, or 3; W is selected from the groupconsisting of

Z¹, Z², and Z³ are independently selected from the group consisting ofCR⁸and N; L is selected from the group consisting of N, O, S, S═O, SO₂,C(O), NC(O), NC(S), OC(O), OC(S), C(NR¹⁰), C(NOR¹⁰), and a covalentbond; R¹ is selected from the group consisting of H, and substituted andunsubstituted arylalkyl, heteroarylalkyl, aryl, heterocyclyl,cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, andalkyl groups; R² is selected from the group consisting of H, andsubstituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl,aryl, and arylalkyl groups; R³ is selected from the group consisting ofH, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups, or R² and R³ may jointogether to form a ring containing at least two N atoms; R⁴ is selectedfrom the group consisting of H, and substituted and unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups; R⁵ is selected from thegroup consisting of H, and substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, awl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups, or R⁴ and R⁵, together withthe nitrogen to which they are bound, form a substituted orunsubstituted heterocyclyl or heteroaryl group; R⁶ and R⁷ may be thesame or different, and are each independently selected from the groupconsisting of H, Cl, I, F, Br, OH, NH₂, CN, NO₂, and substituted andunsubstituted alkoxy, amino, alkyl, alkenyl, alkynyl, alkylamino,dialkylamino, cycloalkyl, heterocyclylamino, heteroarylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl,and heteroarylaminocarbonyl groups: R⁸ is independently selected fromthe group consisting of H, Cl, I, F, Br, OH, NH₂, CN, NO₂, andsubstituted and unsubstituted alkoxy, amino, alkyl, alkenyl, alkynyl,alkylamino, dialkylamino, cycloalkyl, heterocyclylamino,heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; R⁹ andR¹⁰ are independently selected from the group consisting of H, andsubstituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,alkylcarbonyl, and arylcarbonyl groups; and prodrugs thereof,pharmaceutically acceptable salts thereof, stereoisomers thereof,tautomers thereof, hydrates thereof, hydrides thereof, or solvatesthereof.
 3. A compound of formula III

wherein X and Y are independently selected from the group consisting ofCH₂, N, C═O, NR⁹, C═S, S═O, SO₂, O, S, (CR⁶R⁷)_(n), C(═O)—(CR⁶R⁷)_(n),and C(═S)—(CR⁶R⁷)_(n); wherein when X is N, then Y is not N, with theproviso that when X is N, then Y can still be NH; wherein when Y is N,then X is not N, with the proviso that when Y is N, then X can still beNH: wherein when X is CH₂, then Y is not CH₂ wherein when Y is CH₂, thenX is not CH₂ wherein when X is NH, then Y is not NH; wherein when Y isNH, then X is not NH; D is selected from the group consisting of N, andC; L is selected from the group consisting of N, O, S, S═O, SO₂, C(O),NC(O), NC(S), OC(O), OC(S), C(NR¹⁰), C(NOR¹⁰), and a covalent bond; W isselected from the group consisting of

Z¹, Z², and Z³ are independently selected from the group consisting ofCR⁸ and N; R¹ is selected from the group consisting of substituted andunsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups; R² is selected from the group consisting ofH, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkylalkyl, aryl, and arylalkyl groups R³ is selected from thegroup consisting of H, and substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, or R² and R³ mayjoin together to form a ring containing at least two N atoms; R⁴ isselected from the group consisting of H, and substituted andunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; R⁵is selected from the group consisting of H, and substituted andunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, orR⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl or heteroaryl group; R⁶ and R⁷may be the same or different, and are each independently selected fromthe group consisting of H, Cl, I, F, Br, OH, NH₂, CN, NO₂, andsubstituted and unsubstituted alkoxy, amino, alkyl, alkenyl, alkynyl,alkylamino, dialkylamino, cycloalkyl, heterocyclylamino,heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; R⁸ isindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; R⁹ andR¹⁰ are independently selected from the group consisting of H, andsubstituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,alkylcarbonyl, and arylcarbonyl groups; and prodrugs thereof,pharmaceutically acceptable salts thereof, stereoisomers thereof,tautomers thereof, hydrates thereof, hydrides thereof, or solvatesthereof.
 4. A composition comprising the compound according to claim 1and a pharmaceutically acceptable carrier.
 5. A method of treating anMC4-R mediated disease, comprising administering to a subject in needthereof, the compound according to claim
 1. 6. The method according toclaim 5, wherein the disease is obesity or type II diabetes.
 7. Acomposition comprising the compound according to claim 2 and apharmaceutically acceptable carrier.
 8. A method of treating an MC4-Rmediated disease, comprising administering to a subject in need thereof,the compound according to claim
 2. 9. The method according to claim 8,wherein the disease is obesity or type II diabetes.
 10. A compositioncomprising the compound according to claim 3 and a pharmaceuticallyacceptable carrier.
 11. A method of treating an MC4-R mediated disease,comprising administering to a subject in need thereof, the compoundaccording to claim
 3. 12. The method according to claim 11, wherein thedisease is obesity or type II diabetes.
 13. The compound of claim 1 orclaim 3, wherein X and Y are selected from the group consisting of CH₂,and C═O.
 14. The compound of claim 13, wherein D is N.
 15. The compoundof claim 13, wherein X is CH₂ and Y is C═O.
 16. The compound of claim13, wherein X is C═O and Y is CH₂.
 17. The compound of claim 1 or claim3, wherein X is C═O and Y is C═O.
 18. The compound of claim 17, whereinD is N.
 19. The compound of any of claims 1-3, wherein Z¹, Z², and Z³are all CH.
 20. The compound of any of claims 1-3, wherein R¹ is asubstituted or unsubstituted arylalkyl group.
 21. The compound of claim20, wherein R¹ is a 2,4-disubstituted phenethyl group.
 22. The compoundof any of claims 1-3, wherein R² is H.
 23. The compound of any of claims1-3, wherein R⁴ and R⁵, together with the nitrogen to which they arebound, form a substituted or unsubstituted heterocyclyl group.
 24. Thecompound of claim 23, wherein R⁴ and R⁵, together with the nitrogen towhich they are bound, form a substituted or unsubstituted piperazino,morpholino, pyrrolidino, piperidino, homopiperazino, or azepino group.25. The compound of claim 24, wherein R⁴ and R⁵, together with thenitrogen to which they are bound, form a substituted or unsubstitutedpiperazino group.
 26. The compound of claim 25, wherein R⁴ and R⁵,together with the nitrogen to which they are bound, form a piperazinogroup substituted with one or two methyl groups.
 27. The compound of anyof claims 1-3, wherein R³ is selected from substituted or unsubstitutedcycloalkyl, alkenyl, alkyl, or aryl groups.
 28. The compound of any ofclaims 1-3, wherein R³ is selected from substituted or unsubstitutedcyclohexyl, 2-alkylcyclohexyl, 2,2-dialkylcyclohexyl,2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl,2,6-dialkylcyclohexyl, 3,4-dialkylcyclohexyl, 3-alkylcyclohexyl,4-alkylcyclohexyl, 3,3,5-trialkylcyclohexyl, cyclohexylmethyl,2-aminocyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl,2,3-diaminocyclohexyl, 2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl,2,5-diaminocyclohexyl, 2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl,2-alkoxycyclohexyl, 3-alkoxycyclohexyl, 4-alkoxycyclohexyl,2,3-dialkoxycyclohexyl, 2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl,2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl,2-alkylthiocyclohexyl, 3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl,2,3-dialkylthiocyclohexyl, 2,4-dialkylthiocyclohexyl,3,4-dialkylthiocyclohexyl, 2,5-dialkylthiocyclohexyl,2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, cyclopentyl,cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl,2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl,2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl,carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, or decalinyl groups.29. The compound of any of claims 1-3, wherein R³ is selected fromsubstituted or unsubstituted cyclohexyl, 2-methylcyclohexyl,2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl,2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl 3,4-dimethylcyclohexyl,3-methylcyclohexyl, 4-methylcyclohexyl, cyclohex-3-enyl,3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl, 2-methylcycloheptyl,cyclohexylmethyl, isopinocampheyl, 7,7-dimethylnorbornyl,4-isopropylcyclohexyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, or3-methylcycloheptyl groups.
 30. The compound of any of claims 1-3,wherein R⁵ is selected from substituted or unsubstituted alkyl,arylalkyl, or heteroarylalkyl groups.
 31. The compound of any of claims1-3, wherein L is a covalent bond.
 32. The compound of claim 2 or claim3, wherein X is N and Y is NH.
 33. The compound of claim 32, wherein Ais C, and the bond between X and A is a double bond.
 34. The compound ofclaim 32, wherein D is C, and the bond between X and D is a double bond.35. The compound of claim 2 or claim 3, wherein X is NH and Y is N. 36.The compound of claim 35, wherein A is C, and the bond between Y and Ais a double bond.